fractional anisotropic change in pilots and chamber...

Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013

White Matter and Fractional

Anisotropic Change in Pilots

and Chamber Techs

Stephen A. McGuire, M.D.

USAFSAM/FECN

AFMSA/SG9 study grant I-11-10

AFMSA/SG9 study grant I-11-44

Dragon Lady

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Co-Investigators

WHASC/SAMMC

Paul Sherman

Len Profenna

Patrick Grogan

John Sladky

Gerald York

Alan Flower

Univ Maryland Baltimore

Peter Kochunov

HJ Foundation

David Tate

AFRL

Joe Wood

Gary Ford

No financial disclosures

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MRI Abnormalities in 2 Pilots Without Clinical NDCS

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MRI Comparison (1)Clinical vs. Research Sequences

High-resolution 3D FLAIR; clinical 2D FLAIR; clinical 2D T2

White matter hyperintensities (WMH) change readily apparent on high-resolution 3D FLAIR

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MRI Comparison (2)Clinical vs. Research Sequences

High-resolution 3D FLAIR; clinical 2D FLAIR; clinical 2D T2

WMH change readily apparent on high-resolution 3D FLAIR

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MRI – WMH Lesion Volume(n=12 NDCS; 38 no NDCS)

Significant difference in WMH volume in U-2 pilots with vs. without clinical NDCS

No statistical difference in number of WMH

Apparent focal preference for insular region

McGuire et al. Aviat Space Environ Med 2012;83:1117

McGuire et al. Neurology (in press)

ItemAll U-2 pilots

(mean±SD n=50)NDCS U-2

(mean±SD n=12)No NDCS U-2

(mean±SD n=38)p-value

(1-tailed Mann-Whitney)

Total FLAIR vol 1.05±0.54 cm3 1.37±0.79 cm3 0.95±0.37 cm3 0.026

Subcort FLAIR vol 0.07±0.12 cm3 0.13±0.14 cm3 0.05±0.11 cm3 0.059

Insula lobe vol 0.006±0.021 cm3 0.020±0.038 cm3 0.001±0.005 cm3 0.018

Subcort lesion # 3.76±6.10 7.25±10.66 2.66±2.85 0.149

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Comparison of WMH2/10/2013

Significant difference between control (DOC + FSG) and PHY (chamber technicians)

WMH distribution similar in pattern to DCS (U-2 pilots)

No significant difference between PHY vs. DCS

Unrelated to clinical episodes of NDCS

Correlation with exposure hours not yet performed

Item PHY (n=61) DOC+FSG (n=102)p-value


Subcortical WMH vol 0.1479±0.4656 cm3 0.0358±0.0628 cm3 0.021

Subcortical WMH count 7.10±12.44 2.80±3.83 0.017

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Item PHY (n=61) DCS (n=105)p-value


Subcortical WMH vol 0.1479±0.4656 cm3 0.1475±0.2957 cm3 0.356

Subcortical WMH count 7.10±12.44 9.67±18.26 0.191


Comparison U-2 (all) to Doctorate Normative

Images represent super-positioning of all quantitative measurements

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WMH Distribution Pattern

Suggests lesion location directly related to volume of tissue at risk – insula region only exception

Similar preference noted in U-2 ± NDCS

Suggests microembolization (shower) as mechanism

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WMH Location2/15/2013

1.8% (3/167) of DCS+PHY cortical margin lesions

0.4% (6/1500 exposures) arterial gas bubble reported in chamber experiments

1/3 reported NDCS symptoms

No cortical margin lesions in DOC+FSG cohort

Suggests microembolization (< 30 μ) is occurring

Possibly gas bubble – possibly thrombin-platelet aggregate

Number of Subjects

Number of WMH Lesions

Number WMH Lesions at Cortical Junction

DCS 106 1015 2 (1.8% subjects; 0.2% WMH)

PHY 61 433 1 (1.6% subjects; 0.2% WMH)

DOC 77 218 0

FSG 26 68 0

Aviat Space Environ Med 1996; 67:1092-6

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Cortical Thickness(n= 99 DCS; 75 DOC+FSG)

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Cortical Thickness(n= 52 PHY; 75 DOC+FSG)

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Fractional Anisotropy (FA) vs. Age2/18/2013

FA slope vs. age greater in DCS and PHY groups compared to DOC and FSG groups

No correlation to WMH volume

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WMH Volume vs. Average FAAll U-2 Pilots

No correlation between FA and WMH volume

Suggests a more diffuse process than seen by WMH

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WMH Volume vs. Average FANDCS vs. no NDCS

FA decreases with increasing WMH volume

Numbers small – caution in interpretation

Possibly a correlation NDCS vs. no NDCS

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Case Study – FA

FA change with single exposure – 3 mo recovery

6% FA decline (nl < 3%)

14 mountaineers pre/post MRI

Peak altitude 6206 m (21,000 ft)

Significant FA decrease

Third MRI not reported

Zhang et al. High Alt Med Biol 2012;13(2):118-125

2.5-h exposure

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NDCS Hypothesis

Arterial macroembolization relatively uncommon

Microembolization (< 30 μm) dominant mechanism

Venous gas bubbles activate platelets and/or thrombin and/or proinflammatory macroparticles

Randomly distribute to CNS proportional to blood flow

Microemboli possibly gas bubbles or possibly thrombin-platelet aggregates or macroparticles/activated leukocytes

Each exposure activates this mechanism

Degree of FLAIR findings related to intensity of exposure

Reflection of duration/frequency of exposure

Possibly associated with cortical loss and more diffuse axonal injury

Statistical 2nd and 3rd order neurocognitive change

No observed clinical neurocognitive change

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Unanswered Questions

Are the implemented mitigation strategies sufficient?

Is 15,000 ft altitude safe? Where is the threshold?

What other populations are at risk?

What is the temporal evolution of FA injury & WMH lesions?

Is compressive therapy treatment sufficient?

Should antithrombotic or antiplatelet therapy be given either prophylactically or therapeutically?

Is there a significant inflammatory component?

What is the WMH lesion volume threshold beyond which significant neurocognitive impairment will occur?

Is this time-dependent or episodic?

Is this a static process or a progressive process following treatment and/or cessation of exposure?

Is there an increased risk of later cognitive impairment?

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Questions?

Neurologic DCS

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